WO2013150140A1 - New pyrido [3.4-c] [1.9] phenanthroline and 11, 12 dihydropyrido [3.4 -c] [1.9] phenanthroline derivatives and the use thereof, particularly for treating cancer - Google Patents

New pyrido [3.4-c] [1.9] phenanthroline and 11, 12 dihydropyrido [3.4 -c] [1.9] phenanthroline derivatives and the use thereof, particularly for treating cancer Download PDF

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WO2013150140A1
WO2013150140A1 PCT/EP2013/057212 EP2013057212W WO2013150140A1 WO 2013150140 A1 WO2013150140 A1 WO 2013150140A1 EP 2013057212 W EP2013057212 W EP 2013057212W WO 2013150140 A1 WO2013150140 A1 WO 2013150140A1
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compound
phenanthroline
derivatives
general formula
formula
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PCT/EP2013/057212
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German (de)
French (fr)
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Bernd Clement
Christopher Meier
Dieter Heber
Lars Stenzel
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Christian-Albrechts-Universität Zu Kiel
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Priority to JP2015503894A priority Critical patent/JP6129951B6/en
Priority to CA2869426A priority patent/CA2869426C/en
Priority to EP13717459.5A priority patent/EP2834240B1/en
Priority to ES13717459.5T priority patent/ES2636469T3/en
Priority to AU2013244918A priority patent/AU2013244918B2/en
Priority to US14/390,661 priority patent/US9062054B2/en
Publication of WO2013150140A1 publication Critical patent/WO2013150140A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to novel aromatic heterocycles, a process for their preparation and medicaments containing these heterocycles.
  • Another object of the invention is to provide new medicines. Furthermore, it is an object of the invention to provide new medicines, in particular for the treatment of cancer. Another object of the invention is to provide novel pharmaceutical compositions having a pharmaceutically acceptable solubility in water and a preparation process as described below, by means of which the compounds according to the invention can be obtained.
  • the present invention relates to the provision of phenanthroline derivatives of general formulas I and II
  • R Y which may be the same or different, is H, OH, OMe, OEt or halogen; and the general formulas III and IV,
  • R 1 is either equal to a phenyl ring of the formula is that carries at least one substituent R Y in the meta position, wherein R Y , which may be identical or different, is H, OH, OMe, OEt or halogen or equal to a five-membered aromatic heterocycle of the formula
  • W is O, S or NH
  • Z is H, F, Cl, Br, I, NHX, OX, SX,
  • X is H, dimethylaminoalkyl, diethyaminoalkyl, ro (1,3-diazol-1-yl) alkyl, hydroxyalkyl, alkoxyalkyl, thiolalkyl, alkylthioalkyl,
  • alkyl is methyl, ethyl or propyl
  • the invention relates to a process for the preparation of a compound according to the present invention as described above, comprising at least the following steps:
  • R 1 is an H, a cyclic or acyclic, branched or unbranched aliphatic hydrocarbon radical, mono- or polysubstituted, an aromatic carbocyclic or heterocyclic radical which is monosubstituted or polysubstituted, and
  • R 2 and R 3 may be the same or different and is H, alkyloxy, alkyleneoxy, halogen or nitro, and
  • R 4 is an H, a monoamino, alkylamino, dialkylamino, (dialkyl) aminoalkylamine, alkyl, alkoxy, (dialkyl) aminoalkyloxy, hydroxy, hydroxyalkylamino, hydroxyalkyloxy, thiol, (dialkyl) ) is aminoalkylthio, thiolalkyl, alkylthioalkyl or halogen.
  • the present invention relates to a process for preparing a compound as described above, wherein between the two steps (i) and (ii) optionally the process step
  • the present invention relates to a process as described above, wherein the aprotic dipolar solvent is preferably an amide such as dimethylformamide, dimethylacetamide, diethylacetamide, hexamethylphosphoric trisamide or a urea such as tetramethylurea, 1,3-dimethyltetrahydropyrimidin-2-one and 1,3-dimethylimidazolidinone or a Dimethyl sulfoxide and wherein the base is an alkali or alkaline earth hydride such as sodium hydride, alkali amide such as sodium amide, sodium methylacetamide, alkali, alkaline earth or aluminum alkoxide such as potassium tert-butylate, sodium methoxide, sodium ethylate or aluminum ethylate.
  • the base is an alkali or alkaline earth hydride such as sodium hydride, alkali amide such as sodium amide, sodium methylacetamide, alkali, alkaline earth or
  • the procedure is that a reaction of an aldehyde of the formula in which R 1 is both hydrogen, a cyclic or acyclic, branched or unbranched aliphatic hydrocarbon radical which may be mono- or polysubstituted, and also an aromatic carbocyclic or heterocyclic radical which may be monosubstituted or polysubstituted, with 2 moles of a 4-methylpyridine 3-carbonitriles of the formula VI,
  • R and R which may be identical or different, denote an H, an alkyloxy radical, an alkyleneoxy radical, a halogen atom or a nitro group, in the presence of base in an aprotic dipolar solvent to give a 6-amino-1,11,2-dihydropyrido [3,4-c ] [l, 9] phenanthroline of formula VII takes place.
  • Peter C Vollhardt, 3rd edition, 2000 are known to be implemented in one or more steps to the derivatives of the formula I or II or it may according to methods generally known in the art (eg from "Comprehensive Organic Transformations", Richard C. Larock, 1989) with a suitable dehydrating agent in the absence or presence of solvent dehydrogenation to the corre sponding 6-aminopyrido [3,4-c] [l, 9] phenanthrolines of the formula VIII which are subsequently isolated after isolation with the chemical methods corresponding to the respective radicals R 4 in position 6 (Organikum, 21. Edition, 2001, Wiley-VCH; Organic Chemistry, K. Peter C.
  • R is hydrogen, monoamino, alkylamino, dialkylamino, (dialkyl) aminoalkylamino, alkyl, alkoxy, (dialkyl) aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, thiol, ) aminoalkylthio group may be a thiolalkylamino group, a thiolalkylthio group, and a halogen atom.
  • a selection of N-substituted alkylenediamine side chains at position 6 is shown, for example, in genes (Genes et al., Eu.
  • phenanthrolinen of formula VII are preferably amides such as dimethylformamide, dimethylacetamide, diethylacetamide, hexamethyl - Phosphoric acid trisamide or ureas such as tetramethylurea, l, 3-dimethyltetrahydro-pyrimidin-2-one and 1,3-dimethylimidazolidinone or dimethylsulfoxide used.
  • a base for example, can be used:
  • Alkali metal or alkaline earth metal hydrides such as sodium hydride, alkali metal amides such as sodium amide, sodium methylacetamide, alkali metal, alkaline earth metal or aluminum alcoholates such as potassium tert. butylate, sodium methylate, sodium ethylate or aluminum ethylate.
  • the reaction can be carried out as follows: To a solution of the base in a suitable dipolar solvent, under inert gasification, a solution of compound V and VI in the same solvent is slowly added dropwise. After several hours of stirring at 25 - 40 ° C under inert fumigation, the batch is poured onto ice water and the residue filtered off. The filtered solution is extracted by shaking with a suitable organic solvent. The organic phase is largely concentrated and then distilled in vacuo. The combined residues can be purified by recrystallization in a suitable solvent. The 6-amino-1,1,2-dihydropyrido [3,4-c] [l, 9] -phenanthroline VII can then be prepared by general methods (Comprehensive Organic Transformations, Richard C.
  • phenanthroline derivatives which can be synthesized in the 11-position have aliphatic as well as substituted or unsubstituted aromatic radicals. It is surprising that the synthesis is possible by the simple reaction described above, wherein due to the
  • Substance aldehyde a very large range of variation in terms of the products to be obtained. Also at the 6-position one obtains a considerable variability by the possibility of exchanging the amino group for the mentioned radicals. The combination of the two variable positions results in a very large spectrum of compounds and the possibility of building a large library of potentially cytostatic substances.
  • the present invention also relates to compounds obtainable by a process as described above.
  • the invention relates to the above compounds for use as medicaments, in particular for use in cancer therapy.
  • a compound of the invention as described above is for use in the treatment of a disease selected from a group consisting of microbial, fungicidal, viral and / or inflammatory diseases.
  • the invention relates to an inventive compound as described above for use in the treatment of cancer.
  • the cancer is selected from a group consisting of leukemia, melanoma or breast cancer.
  • the present invention relates to a pharmaceutical composition containing at least one of the compounds described above in combination with a suitable excipient.
  • the derivatives were first tested in a concentration of 1 ⁇ on the 60 cell lines. Growth inhibition was found for several derivatives. Surprisingly, the compounds according to the invention exhibited activities which are outside the category of antitumor compounds investigated in a similar manner, so that a completely new spectrum of action is achieved here.
  • Table I shows the results of this test, selected for 7 different derivatives of phenanthroline derivatives of the invention of formulas I and II with different residues in the 11-position and in the 6-position.
  • the respective radicals are shown in the first two lines.
  • the left column shows the cell lines used from 3 selected tumor types, leukemia, melanoma and breast cancer.
  • the table makes statements about growth-inhibiting effects of the corresponding derivatives with their different residues.
  • the first three derivatives show marked growth inhibition on the cells of the tumor types selected for the example, while the remaining 4 derivatives have no to very little growth-inhibiting effects on these cells. From this it can be deduced that a 3-halophenyl radical in the 11 position is essential for the growth-inhibiting effect of the phenanthroline derivatives of the formulas I and II. Neither derivatives with halogen atoms in the 2- or 4-position (in the example 2-bromophenyl, or 4-bromophenyl), nor derivatives with other functional groups in the 3-position of Phenyl rings, nor the unsubstituted phenyl ring show growth-inhibiting effects to this extent.
  • Table II shows the results of this test, selected for 5 different derivatives of phenanthroline derivatives of the formula III according to the invention with different radicals in the 11-position.
  • the residues in position 11 are shown in the first line.
  • the left column shows the cell lines used from 3 selected tumor types, leukemia, melanoma and breast cancer.
  • the table makes statements about growth-inhibiting effects of the corresponding derivatives with their different residues.
  • Table II shows the best results in terms of a growth-inhibitory effect for the derivative with the trimethoxyphenyl radical in the 11-position.
  • the derivative with only one methoxy group in the meta position also achieves considerable growth inhibition.
  • the 11-phenyl derivative has only a slight effect, while a substitution in the o-position on the example of the 2,3-dimethoxyphenyl derivative proves to be disadvantageous. From this it can be deduced that at least in the meta position of the 11-phenyl ring, a substituent must be present. From the results of Table I it can be expected that the replacement of methoxy by halogen in the meta position will also be good growth-inhibiting effects.
  • the 11-furyl derivative shows good cytotoxic effects as a representative of a seeded heteroaromatic compound.
  • the phenanthrolder derivatives according to the invention tested here have selectivities for certain tumor types. Most pronounced is a growth inhibitory effect on tumor cells of leukemia. Furthermore, a certain selectivity for tumor cells of the melanoma and mammary carcinoma (breast cancer) can be seen. These results are representative of all 60 cell lines. Furthermore, among the most potent compounds, dose-response relationships for 5 concentrations have been determined. The GI 5 o (growth inhibition 50%) here describes the concentration of test substance required for inhibiting cell growth by 50%.
  • MGJVIID mean graph-midpoint
  • P4 6-amino-1,11,12-dihydropyrido [3,4-c] [l, 9] phenanthroline
  • P5 6-amino-1- (3-bromophenyl) -1,12-dihydro-pyrido- [3,4-c] [l, 9] phenanthroline
  • P5-0 1 l- (3-bromophenyl) -6-oxo-5, 6, 11, 12- tetrahydropyrido [3,4-c] [l, 9] phenanthroline
  • P16 6-amino-1- (3-chlorophenyl) -1,12-dihydropyrido [3,4-c] [l, 9] phenanthroline
  • P26 6-Amino-l- (3,4-di-chlorophenyl) -1,12-dihydropyrido [3,4-c] - [1, 9] phenanthroline.
  • Fagaronin was tested, a vegetable benzo [c] phenanthridine alkaloid, which is considered as a lead compound for the development of synthetic benzo [c] phenanthridine derivatives (Pommier, Y. Nat Rev. Cancer, 6, (2006) , 789; Pommier, Y. Chem. Rev. 109, (2009), 2984). It should be noted that all derivatives of the phenathrolines according to the invention, for which dose-response curves have been determined, have a better growth-inhibiting effect than the natural product fagaronin.
  • FIG. 1-9 Illustrative of 6-amino-1- (3-bromophenyl) -1,12-dihydropyrido [34-c] [l, 9] phenanthroline are the dose-response curves shown in Figures 1-9.
  • the nine different illustrations contain the different cancers. In each case, the percentage growth is plotted as a function of the concentration of the compound (as logio of the molar concentrations).
  • the individual curves of each cancer are different cell lines of this cancer form, which appear as legends in their usual abbreviations. Horizontal lines in the figures mean percent growth +100, +50, 0, -50, -100. 100% growth means e.g. no difference to growth after two days without added substance. It can be seen from the individual curves that the percentage growth decreases with increasing concentrations of the substance.
  • a particular advantage of the phenanthroline derivatives according to the invention is their improved water solubility in comparison to the 6-aminobenzo [c] phenanthridines.
  • pH 7.4 solubilities in the lower micromolar range ( ⁇ 1-15 ⁇ ) could be found for numerous derivatives, the solubility of the 6-Aminobenzo [c] phenanthridine at this pH is predominantly in the nanomolar range.
  • logP values of the phenanthroline derivatives according to the invention were determined as a measure of the lipophilicity of the substance class.
  • Six different 6-amino-1,12-dihydropyrido [3,4-c] [l, 9] phenanthrolines with different residues in position 11 were compared with the corresponding benzo [c] phenanthridines.
  • Figure 11 shows the logP values on the y-axis plotted against the derivatives differing in the six named residues in the 11-position, respectively, for the two substance classes being compared.
  • the mean value (MW) is plotted.
  • the examined derivatives according to the invention are all within the limits of the "Rule of Five" and are then suitable as orally applicable drugs, e.g. in the form of solutions, tablets, capsules, etc.
  • the figures show dose-response curves of 9 different tumor types from the 5-dose assay (NCI) for 6-amino-1- (3-bromophenyl) -II, 12-dihydropyrido [3,4-c] [l , 9] phenanthroline.
  • Fig. 1 Dose-response curves for leukemia tumors from the 5-dose assay (NCI) for 6-
  • Fig. 2 Dose-response curves for non-small cell lung carcinomas from the 5-dose assay (NCI) for 6-amino-1- (3-bromophenyl) -II, 12-dihydropyrido [3,4-c] [1, 9] phenanthroline
  • FIG. 3 dose-response curves for colon carcinomas from the 5-dose assay (NCI) for 6-amino
  • FIG. 4 dose-response curves for CNS cancer from the 5-dose assay (NCI) for 6-amino-1-ol
  • FIG. 5 dose-response curves for melanomas from the 5-dose assay (NCI) for 6-amino-1-ol
  • Fig. 6 Dose-response curves for renal cell carcinomas from the 5-dose assay (NCI) for 6-
  • FIG. 7 dose-response curves for ovarian carcinomas from the 5-dose assay (NCI) for 6-
  • Fig. 8 Dose-response curves for prostate cancer from the 5-dose assay (NCI) for 6-
  • FIG. 9 dose-response curves for mammary carcinomas from the 5-dose assay (NCI) for 6-
  • Fig. 10 pH-dependent solubilities of the 6-amino-11,12-dihydropyrido [3,4-c] [1, 9] phenanthrolines
  • Fig. 11 LogP values as a function of the residues in 11 position

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Abstract

The invention relates to new phenanthroline derivatives of the general formulae (I), (II), (III) or (IV) as a drug for treating cancer or a disease selected from the group consisting of microbial, fungal, viral and/or inflammatory diseases, and methods for producing said compounds.

Description

NEUE PYRIDO [3,4-C] [1 ,9] PHENANTHROLIN- UND 11 ,12 -DIHYDROPYRIDO  NEW PYRIDO [3,4-C] [1, 9] PHENANTHROLIN AND 11, 12 -DIHYDROPYRIDO
[3,4-C] [1 ,9] PHENANTHROLIN- DERIVATE UND IHRE VERWENDUNG,  [3,4-C] [1, 9] PHENANTHROLIN DERIVATIVES AND THEIR USE,
INSBESONDERE, ZUR BEHANDLUNG VON KREBS  ESPECIALLY, FOR THE TREATMENT OF CANCER
Die vorliegende Erfindung betrifft neue aromatische Heterocyclen, ein Verfahren zu deren Herstellung sowie Arzneimittel, enthaltend diese Heterocyclen. The present invention relates to novel aromatic heterocycles, a process for their preparation and medicaments containing these heterocycles.
Viele Krebserkrankungen sind bislang nicht durch selektiv wirkende Wirkstoffe therapierbar. Nach Angaben der World Health Organization (WHO) wurde weltweit im Jahr 2000 bei ca. 10 Millionen Menschen Krebs diagnostiziert, ca. 6 Millionen verstarben (World Cancer Report 2003, www.iarc.fr/IARCPress/pdfs/wcr/WorldCancerReport.pdf ). Nach Schätzung der WHO wird die Zahl der durch Krebserkrankungen hervorgerufenen Todesfälle bis 2030 auf ca. 11,5 Millionen pro Jahr ansteigen (Worlds Health Statistics - 2007, www.who.int whosis/whostat2007_10-highlights.pdf). I m Hinblick auf die große Anzahl von Menschen, die an Krebs erkrankt sind, die ungünstige Prognose für die Heilung bestimmter Krebsarten aufgrund der schlechten Wirksamkeit bisheriger Medikamente, Nebenwirkungen und Resistenzentwicklung gegenüber eingesetzten Arzneimitteln besteht ein dringender Bedarf an neuen Krebsmedikamenten. Many cancers have not been treated by selective drugs. According to the World Health Organization (WHO), approximately 10 million people worldwide were diagnosed with cancer in 2000, and approximately 6 million died (World Cancer Report 2003, www.iarc.fr/IARCPress/pdfs/wcr/WorldCancerReport.pdf) , The WHO estimates that the number of cancer deaths will increase to approximately 11.5 million per year by 2030 (Worlds Health Statistics - 2007, www.who.int whosis / whostat2007_10-highlights.pdf). In view of the large number of people suffering from cancer, the unfavorable prognosis for the cure of certain cancers due to the poor efficacy of previous drugs, side effects and resistance to drugs used, there is an urgent need for new cancer drugs.
Aus der DE 195 38 088 AI sind 6-Aminobenzo[c]phenanthridine bekannt, welche teilweise über antitumorale, antimikrobielle, antifungizide, antivirale und antiinflammatorische Eigenschaften verfügen. Die genannten Verbindungen weisen aber noch Nachteile im pharmakologischen Profil insbesondere der geringen Wasserlöslichkeit auf. DE 195 38 088 A1 discloses 6-aminobenzo [c] phenanthridines, some of which have antitumoral, antimicrobial, antifungal, antiviral and antiinflammatory properties. The compounds mentioned, however, still have disadvantages in the pharmacological profile, in particular the low water solubility.
Es ist daher Aufgabe der Erfindung neue Arzneimittel zur Verfügung zu stellen. Des Weiteren ist es Aufgabe der Erfindung neue Arzneimittel insbesondere zur Therapie gegen Krebserkrankungen zur Verfügung zu stellen. Eine weitere Aufgabe der Erfindung ist es neue Arzneimittel mit einer pharmazeutisch akzeptablen Wasserlöslichkeit zur Verfügung zu stellen sowie ein Herstellungsverfahren wie nachstehend beschrieben, durch die die erfindungsmäßen Verbindungen erhalten werden können. It is therefore an object of the invention to provide new medicines. Furthermore, it is an object of the invention to provide new medicines, in particular for the treatment of cancer. Another object of the invention is to provide novel pharmaceutical compositions having a pharmaceutically acceptable solubility in water and a preparation process as described below, by means of which the compounds according to the invention can be obtained.
Die Aufgabe wird durch die in den Ansprüchen und der vorliegenden Beschreibung gekennzeichneten Ausführungsformen gelöst. Die Unteransprüche und Beispiele geben vorteilhafte Ausgestaltungen der Erfindung an. In einem Aspekt betrifft die vorliegende Erfindung die Bereitstellung von Phenanthrolinderivate der allgemeinen Formeln I und II The object is achieved by the embodiments characterized in the claims and the present description. The subclaims and examples indicate advantageous embodiments of the invention. In one aspect, the present invention relates to the provision of phenanthroline derivatives of general formulas I and II
Figure imgf000004_0001
Figure imgf000004_0001
ist, der mindestens einen Substituenten R ausgewählt aus der Gruppe Cl, Br oder I in meta-Stellung trägt, wobei RY, welches gleich oder verschieden sein kann, gleich H, OH, OMe, OEt oder Halogen ist; sowie der allgemeinen Formeln III und IV, is that carries at least one substituent R selected from the group Cl, Br or I in the meta position, wherein R Y , which may be the same or different, is H, OH, OMe, OEt or halogen; and the general formulas III and IV,
Figure imgf000004_0002
Figure imgf000004_0002
wobei R1 entweder gleich einem Phenylring der Formel
Figure imgf000005_0001
ist, der mindestens einen Substituenten RY in meta-Stellung trägt, wobei RY, welches gleich oder verschieden sein kann, gleich H, OH, OMe, OEt oder Halogen ist oder gleich einem fünfghedrigen aromatischen Heterocyclus der Formel where R 1 is either equal to a phenyl ring of the formula
Figure imgf000005_0001
is that carries at least one substituent R Y in the meta position, wherein R Y , which may be identical or different, is H, OH, OMe, OEt or halogen or equal to a five-membered aromatic heterocycle of the formula
Figure imgf000005_0002
ist, wobei W gleich O, S oder NH ist; und
Figure imgf000005_0002
where W is O, S or NH; and
wobei Z gleich H, F, Cl, Br, I, NHX, OX, SX, where Z is H, F, Cl, Br, I, NHX, OX, SX,
wobei X gleich einem H, Dimethylaminoalkyl-, Diethyaminoalkyl-, ro-(l,3-diazol-l-yl)-alkyl-, Hydroxyalkyl-, Alkoxyalkyl-, Thiolalkyl-, Alkylthioalkylgruppe ist, wherein X is H, dimethylaminoalkyl, diethyaminoalkyl, ro (1,3-diazol-1-yl) alkyl, hydroxyalkyl, alkoxyalkyl, thiolalkyl, alkylthioalkyl,
wobei Alkyl gleich Methyl, Ethyl oder Propyl where alkyl is methyl, ethyl or propyl
und wobei A gleich O oder S ist, and where A is O or S,
sowie deren pharmazeutisch verträgliche Salze, Solvate und Prodrugs. and their pharmaceutically acceptable salts, solvates and prodrugs.
In einem weiteren Aspekt betrifft die Erfindung ein Verfahren zur Herstellung einer Verbindung gemäß der vorliegenden Erfindung wie vorstehend beschrieben, umfassend mindestens die folgenden Schritte: In a further aspect, the invention relates to a process for the preparation of a compound according to the present invention as described above, comprising at least the following steps:
(i) Umsetzung von substituierten Aldehyden der allgemeinen Formel R1 - CHO (V) mit substituierten 4-Methylpyridin-3-carbonitrilen der allgemeinen Formel (i) Reaction of substituted aldehydes of the general formula R 1 - CHO (V) with substituted 4-methylpyridine-3-carbonitriles of the general formula
Figure imgf000005_0003
in aprotischen bipolaren Lösungsmitteln in Gegenwart von Basen zu einer Verbindung der allgemeinen Formel 2
Figure imgf000005_0003
in aprotic bipolar solvents in the presence of bases to give a compound of the general formula 2
Figure imgf000006_0001
Figure imgf000006_0001
(ii) Isolierang der Produkte und Derivatisierung an Position 6 unter Einfügen der Reste R4 zu den Derivaten mit A- oder Z-Substitution in 6-Position, gemäß der Formeln I bis IV, wobei R1 ein H, ein cyclischer oder acyclischer, verzweigter oder unverzweigter aliphatischer Kohlenwasserstoffrest, einfach oder mehrfach substituiert, ein aromatischer carbocyclischer oder heterocyclischer Rest, einfach oder mehrfach substituiert ist, und (ii) isolating the products and derivatizing at position 6 with the substitution of R 4 for the derivatives with A or Z substitution in position 6, according to formulas I to IV, where R 1 is an H, a cyclic or acyclic, branched or unbranched aliphatic hydrocarbon radical, mono- or polysubstituted, an aromatic carbocyclic or heterocyclic radical which is monosubstituted or polysubstituted, and
R2 und R3, gleich oder verschieden sein können und ein H, Alkyloxyrest, Alkylenoxyrest, Halogenatom oder eine Nitrogruppe ist, und R 2 and R 3 may be the same or different and is H, alkyloxy, alkyleneoxy, halogen or nitro, and
R4 ein H, eine Monoamino-, Alkylamino-, Dialkylamino-, (Dialkyl-)aminoalkylamin-, Alkyl-, Alkoxy-, (Dialkyl-)aminoalkyloxy-, Hydroxy-, Hydroxyalkylamino-, Hydroxyalkyloxy-, Thiol-, (Dialkyl-) aminoalkylthio-, Thiolalkyl-, Alkylthioalkylgruppe oder ein Halogenatom ist. R 4 is an H, a monoamino, alkylamino, dialkylamino, (dialkyl) aminoalkylamine, alkyl, alkoxy, (dialkyl) aminoalkyloxy, hydroxy, hydroxyalkylamino, hydroxyalkyloxy, thiol, (dialkyl) ) is aminoalkylthio, thiolalkyl, alkylthioalkyl or halogen.
Die anschließende Derivatisierung an Position 6 unter Einfügen der Reste R4 zu den Derivaten mit A - oder Z-Substitution in 6-Position entsprechend Verfahrensschritt (ii) führt zu den erfindungsgemäßen Verbindungen wie in der allgemeinen Formel III oder IV dargestellt. The subsequent derivatization at position 6 with the addition of the radicals R 4 to the derivatives with A or Z substitution in the 6-position corresponding to process step (ii) leads to the compounds according to the invention as shown in the general formula III or IV.
Daher betrifft die vorliegende Erfindung ein Verfahren zur Herstellung einer Verbindung wie vorstehend beschrieben, wobei zwischen den beiden Schritten (i) und (ii) optional der Verfahrensschritt Therefore, the present invention relates to a process for preparing a compound as described above, wherein between the two steps (i) and (ii) optionally the process step
(i.a.) Dehydrierung und Isolierung der hieraus resultierenden Produkte der allgemeinen Formel
Figure imgf000007_0001
eingeführt sein kann. (ia) dehydration and isolation of the resulting products of the general formula
Figure imgf000007_0001
can be introduced.
Insbesondere betrifft die vorliegende Erfindung ein wie oben beschriebenes Verfahren, wobei das aprotische dipolare Lösungsmittel vorzugsweise ein Amid wie Dimethylformamid, Dimethylacetamid, Diethylacetamid, Hexamethylphosphorsäuretrisamid oder ein Harnstoff wie Tetramethylharnstoff, 1,3- Dimethyltetrahydropyrimidin-2-οη und 1,3-Dimethylimidazolidinon oder ein Dimethylsulfoxid ist und wobei die Base ein Alkali- oder Erdalkalihydrid wie Natriumhydrid, Alkaliamid wie Natriumamid, Natriummethylacetamid, Alkali-, Erdalkali- oder Aluminiumalkoholat wie Kalium-tert-butylat, Natriummethylat, Natriumethylat oder Aluminiumethylat ist. In particular, the present invention relates to a process as described above, wherein the aprotic dipolar solvent is preferably an amide such as dimethylformamide, dimethylacetamide, diethylacetamide, hexamethylphosphoric trisamide or a urea such as tetramethylurea, 1,3-dimethyltetrahydropyrimidin-2-one and 1,3-dimethylimidazolidinone or a Dimethyl sulfoxide and wherein the base is an alkali or alkaline earth hydride such as sodium hydride, alkali amide such as sodium amide, sodium methylacetamide, alkali, alkaline earth or aluminum alkoxide such as potassium tert-butylate, sodium methoxide, sodium ethylate or aluminum ethylate.
Es hat sich in den erfindungsgemäß durchgeführten Experimenten gezeigt, dass es überraschenderweise möglich ist, die erfindungsgemäßen Phenanthrolinderivate durch einfache Umsetzung von entsprechend substituierten Aldehyden mit entsprechend substituierten 4-Methylpyridin-3-carbonitrilen zu erhalten. It has been shown in the experiments carried out according to the invention that it is surprisingly possible to obtain phenanthroline derivatives of the invention by simple reaction of appropriately substituted aldehydes with appropriately substituted 4-methylpyridine-3-carbonitriles.
Der Reaktionsablauf lässt sich wie folgt darstellen: The course of the reaction can be represented as follows:
Figure imgf000007_0002
Im Einzelnen wird dabei so vorgegangen, dass eine Umsetzung von einem Aldehyd der Formel
Figure imgf000008_0001
worin R1 sowohl Wasserstoff, ein cyclischer oder acyclischer, verzweigter oder unverzweigter aliphatischer Kohlenwasserstoffrest, der einfach oder mehrfach substituiert sein kann, als auch ein aromatischer carbocyclischer oder heterocyclischer Rest, der einfach oder mehrfach substituiert sein kann, mit 2 Mol eines 4-Methylpyridin-3-carbonitrils der Formel VI,
Figure imgf000007_0002
In detail, the procedure is that a reaction of an aldehyde of the formula
Figure imgf000008_0001
in which R 1 is both hydrogen, a cyclic or acyclic, branched or unbranched aliphatic hydrocarbon radical which may be mono- or polysubstituted, and also an aromatic carbocyclic or heterocyclic radical which may be monosubstituted or polysubstituted, with 2 moles of a 4-methylpyridine 3-carbonitriles of the formula VI,
Figure imgf000008_0002
Figure imgf000008_0002
VI wobei R und R ; die gleich oder verschieden sein können, ein H, einen Alkyloxyrest, einen Alkylenoxyrest, ein Halogenatom oder eine Nitrogruppe bedeuten, in Gegenwart von Base in einem aprotischen dipolaren Lösungsmittel zu einem 6-Amino-l l,12-dihydropyrido[3,4-c][l,9]phenanthrolin der Formel VII erfolgt. VI where R and R ; which may be identical or different, denote an H, an alkyloxy radical, an alkyleneoxy radical, a halogen atom or a nitro group, in the presence of base in an aprotic dipolar solvent to give a 6-amino-1,11,2-dihydropyrido [3,4-c ] [l, 9] phenanthroline of formula VII takes place.
Nach Isolierung durch Ausfällen der freien Base, Filtration und anschließender Aufreinigung, beispielsweise Umkristallisation {Organikum, 21. Auflage, 2001, Wiley-VCH) können diese Derivate der Formel VII mit den für die jeweiligen Reste R4 an Position 6 entsprechenden chemischen Methoden (Diazotierung, Umsetzung von Carbonsäurederivaten mit anorganischen Säurechloriden, nukleophile Substitution am Aromaten, Synthese von Thionen/Thiolen und Reduktionsreaktionen, wie z.B. Entschwefelungen), welche dem Fachmann beispielsweise aus Organikum, 21. Auflage, 2001, Wiley- VCH oder Organische Chemie, K. Peter C. Vollhardt, 3. Auflage, 2000 bekannt sind, in einem oder mehreren Schritten zu den Derivaten mit der Formel I oder II umgesetzt werden oder es kann nach dem Fachmann allgemein bekannten Methoden (z.B. aus "Comprehensive Organic Transformations", Richard C. Larock, 1989) mit einem geeigneten Dehydrierungsmittel in Ab- oder Anwesenheit von Lösungsmittel eine Dehydrierung zu den entsprechenden 6-Aminopyrido[3,4-c][l,9]phenanthrolinen der Formel VIII erfolgen, welche im Anschluss nach Isolierung mit den für die jeweiligen Reste R4 an Position 6 entsprechenden, dem Fachmann bekannten chemischen Methoden (Organikum, 21. Auflage, 2001, Wiley-VCH; Organische Chemie, K. Peter C. Vollhardt, 3. Auflage, 2000), in einem oder mehreren Schritten zu den Derivaten mit der Formel III oder IV umgesetzt werden können, wobei der Rest R ein Wasserstoffatom, eine Monoaminogruppe, eine Alkylaminogruppe, eine Dialkylaminogruppe, eine (Dialkyl-)aminoalkylamingruppe, eine Alkylgruppe, eine Alkoxygruppe, eine (Dialkyl-)aminoalkyloxygruppe, eine Hydroxygruppe, eine Hydroxyalkylaminogruppe, eine Hydroxyalkyloxygruppe, eine Thiolgruppe, eine (Dialkyl-) aminoalkylthiogruppe eine Thiolalkylaminogruppe, eine Thiolalkylthiogruppe, sowie ein Halogenatom sein kann. Eine Auswahl an N-substituierten Alkylendiamin- Seitenketten an Position 6 ist z.B. bei Genes dargestellt (Genes et al, Eu. J. Med. Chem. (46), 2011, 2117-2131). Die Einfuhr von Sauerstoff-, Schwefel- und Kohlenstoffnukleophilen wird z.B. von Cherng beschrieben (Cherng, Tetrahedron 58, 2002, 4931- 4935), des Weiteren gelten die allgemein gültigen Methoden der nukleophilen Substitution am Aromaten, dem Fachmann bekannt aus Organikum, 21. Auflage, 2001, Wiley-VCH oder Organische Chemie, K. Peter C. Vollhardt, 3. Auflage, 2000. After isolation by precipitation of the free base, filtration and subsequent purification, for example recrystallization {Organikum, 21st edition, 2001, Wiley-VCH), these derivatives of the formula VII with the appropriate for the respective radicals R 4 at position 6 chemical methods (diazotization , Reaction of carboxylic acid derivatives with inorganic acid chlorides, nucleophilic substitution at the aromatic, synthesis of thiones / thiols and reduction reactions, such as desulfurization), which the skilled worker for example from Organikum, 21st Edition, 2001, Wiley-VCH or Organic Chemistry, K. Peter C Vollhardt, 3rd edition, 2000 are known to be implemented in one or more steps to the derivatives of the formula I or II or it may according to methods generally known in the art (eg from "Comprehensive Organic Transformations", Richard C. Larock, 1989) with a suitable dehydrating agent in the absence or presence of solvent dehydrogenation to the corre sponding 6-aminopyrido [3,4-c] [l, 9] phenanthrolines of the formula VIII which are subsequently isolated after isolation with the chemical methods corresponding to the respective radicals R 4 in position 6 (Organikum, 21. Edition, 2001, Wiley-VCH; Organic Chemistry, K. Peter C. Vollhardt, 3rd edition, 2000), in one or more steps to the derivatives of the formula III or IV can be implemented, wherein the R is hydrogen, monoamino, alkylamino, dialkylamino, (dialkyl) aminoalkylamino, alkyl, alkoxy, (dialkyl) aminoalkyloxy, hydroxy, hydroxyalkyl, hydroxyalkyloxy, thiol, ) aminoalkylthio group may be a thiolalkylamino group, a thiolalkylthio group, and a halogen atom. A selection of N-substituted alkylenediamine side chains at position 6 is shown, for example, in genes (Genes et al., Eu. J. Med. Chem. (46), 2011, 2117-2131). The import of oxygen, sulfur and carbon nucleophiles is described, for example, by Cherng (Cherng, Tetrahedron 58, 2002, 4931-4935), furthermore, the generally valid methods of nucleophilic substitution on aromatics, known to those skilled in the art from Organikum, 21st edition , 2001, Wiley-VCH or Organic Chemistry, K. Peter C. Vollhardt, 3rd Edition, 2000.
Als aprotische dipolare Lösungsmittel für die erfindungsgemäße Reaktion zur Herstellung von entsprechend substituierten 6-Amino-l l,12-dihydropyrido[3,4-c][l,9]phenanthrolinen der Formel VII sind vorzugsweise Amide wie Dimethylformamid, Dimethylacetamid, Diethylacetamid, Hexamethyl- phosphorsäure-trisamid oder Harnstoffe wie Tetramethylharnstoff, l,3-Dimethyltetrahydro-pyrimidin-2- on und 1,3-Dimethylimidazolidinon oder Dimethylsulfoxid verwendbar. As aprotic dipolar solvents for the reaction according to the invention for the preparation of correspondingly substituted 6-amino-l l, 12-dihydropyrido [3,4-c] [l, 9] phenanthrolinen of formula VII are preferably amides such as dimethylformamide, dimethylacetamide, diethylacetamide, hexamethyl - Phosphoric acid trisamide or ureas such as tetramethylurea, l, 3-dimethyltetrahydro-pyrimidin-2-one and 1,3-dimethylimidazolidinone or dimethylsulfoxide used.
Als Base können beispielsweise eingesetzt werden: As a base, for example, can be used:
Alkali- oder Erdalkalihydride, wie Natriumhydrid, Alkaliamide wie Natriumamid, Natrium- methylacetamid, Alkali-, Erdalkali- oder Aluminiumalkoholate wie Kalium-tert. -butylat, Natriummethylat, Natriumethylat oder Aluminiumethylat. Alkali metal or alkaline earth metal hydrides, such as sodium hydride, alkali metal amides such as sodium amide, sodium methylacetamide, alkali metal, alkaline earth metal or aluminum alcoholates such as potassium tert. butylate, sodium methylate, sodium ethylate or aluminum ethylate.
Die Reaktion kann wie folgt durchgeführt werden: Zu einer Lösung der Base in einem geeigneten dipolaren Lösungsmittel wird unter Inertbegasung eine Lösung der Verbindung V und VI in demselben Lösungsmittel langsam zugetropft. Nach mehrstündigem Rühren bei 25 - 40 °C unter Inertbegasung wird der Ansatz auf Eiswasser gegossen und der Rückstand abfiltriert. Die abfiltrierte Lösung wird mit einem geeigneten organischen Lösungsmittel ausgeschüttelt. Die organische Phase wird weitgehend eingeengt und anschließend im Vakuum destilliert. Die vereinigten Rückstände können durch Umkristallisation in einem geeigneten Lösungsmittel aufgereinigt werden. Das 6-Amino-l l,12- dihydropyrido[3,4-c][l,9]-phenanthrolin VII kann dann nach allgemein gültigen Methoden (Comprehensive Organic Transformations, Richard C. Larock, 1989) mit einem geeigneten Dehydrierungsmittel in Gegenwart oder Abwesenheit eines inerten Lösungsmittels zum 6-Amino- pyrido[3,4-c][l,9]phenanthrolin VIII dehydriert werden. Die Aminogruppe in 6-Position kann in einem oder mehreren Schritten mit allgemein gültigen chemischen Methoden (z.B Organikum, 21. Auflage, 2001, Wiley-VCH; Organische Chemie, K. Peter C. Vollhardt, 3. Auflage, 2000) gegen die oben genannten genannten Reste R ausgetauscht werden, so dass man zu den Formeln I oder II, bzw. für die 11,12-dehydrierten Derivate zu den Formeln III oder IV gelangt. The reaction can be carried out as follows: To a solution of the base in a suitable dipolar solvent, under inert gasification, a solution of compound V and VI in the same solvent is slowly added dropwise. After several hours of stirring at 25 - 40 ° C under inert fumigation, the batch is poured onto ice water and the residue filtered off. The filtered solution is extracted by shaking with a suitable organic solvent. The organic phase is largely concentrated and then distilled in vacuo. The combined residues can be purified by recrystallization in a suitable solvent. The 6-amino-1,1,2-dihydropyrido [3,4-c] [l, 9] -phenanthroline VII can then be prepared by general methods (Comprehensive Organic Transformations, Richard C. Larock, 1989) with a suitable dehydrating agent in the presence or absence of an inert solvent to the 6-aminopyrido [3,4-c] [l, 9] phenanthroline VIII. The amino group in the 6-position can be used in one or more steps with generally valid chemical methods (eg, Organikum, 21st Edition, 2001, Wiley-VCH, Organic Chemistry, K. Peter C. Vollhardt, 3rd Edition, 2000) against the above said radicals R are exchanged, so that one arrives at the formulas I or II, or for the 11,12-dehydrogenated derivatives to the formulas III or IV.
Besonders hervorzuheben beim erfindungsgemäßen Verfahren ist, dass sich hiermit Phenanthrolinderivate synthetisieren lassen, die in 11 -Stellung sowohl aliphatische, als auch substituierte oder unsubstituierte aromatische Reste aufweisen. Es ist überraschend, dass die Synthese durch die vorstehend beschriebene einfache Reaktion möglich ist, wobei aufgrund der einzusetzenden Particularly noteworthy in the process according to the invention is that phenanthroline derivatives which can be synthesized in the 11-position have aliphatic as well as substituted or unsubstituted aromatic radicals. It is surprising that the synthesis is possible by the simple reaction described above, wherein due to the
Ausgangssubstanz Aldehyd eine sehr große Variationsbreite in Bezug auf die zu erhaltenden Produkte besteht. Auch an der 6-Position erhält man eine beachtliche Variabilität durch die Möglichkeit des Austauschs der Aminogruppe gegen die genannten Reste. Durch die Kombination der beiden variablen Positionen ergibt sich ein sehr großes Spektrum an Verbindungen und die Möglichkeit des Aufbaus einer großen Bibliothek potentiell zytostatisch wirksamer Substanzen. Substance aldehyde a very large range of variation in terms of the products to be obtained. Also at the 6-position one obtains a considerable variability by the possibility of exchanging the amino group for the mentioned radicals. The combination of the two variable positions results in a very large spectrum of compounds and the possibility of building a large library of potentially cytostatic substances.
In einem Teilaspekt betrifft die vorliegende Erfindung auch Verbindungen, welche durch ein Verfahren wie vorstehend beschrieben erhältlich sind. In one aspect, the present invention also relates to compounds obtainable by a process as described above.
In einem weiteren Teilaspekt betrifft die Erfindung die vorstehenden Verbindungen zur Verwendung als Arzneimittel, insbesondere zur Verwendung in der Krebstherapie. In a further aspect, the invention relates to the above compounds for use as medicaments, in particular for use in cancer therapy.
Bevorzugt ist eine erfindungsgemäße Verbindung wie oben beschreiben zur Verwendung bei der Behandlung einer Erkrankung ausgewählt aus einer Gruppe bestehend aus mikrobiellen, fungiziden, viralen und/oder inflamatorischen Erkrankungen. Preferably, a compound of the invention as described above is for use in the treatment of a disease selected from a group consisting of microbial, fungicidal, viral and / or inflammatory diseases.
Ferner betrifft die Erfindung in einem Teilaspekt eine erfindungsmäßige Verbindung wie vorstehend beschrieben zur Verwendung bei der Behandlung von Krebs. Furthermore, in one aspect, the invention relates to an inventive compound as described above for use in the treatment of cancer.
Bevorzugt ist der Krebs ausgewählt ist aus einer Gruppe bestehend aus Leukämie, Melanom oder Mammakarzinom. Preferably, the cancer is selected from a group consisting of leukemia, melanoma or breast cancer.
Des Weiteren betrifft die vorliegende Erfindung eine pharmazeutische Zusammensetzung enthaltend mindestens eine der vorstehend beschriebenen Verbindung in Kombination mit einem geeigneten Hilfsstoff. Furthermore, the present invention relates to a pharmaceutical composition containing at least one of the compounds described above in combination with a suitable excipient.
Es hat sich in den erfindungsgemäß durchgeführten Experimenten gezeigt, dass die vorstehend beschriebenen Phenanthrolinderivate antitumorale Eigenschaften besitzen. Aufgrund ihrer strukturellen Ähnlichkeit ist anzunehmen, dass sie wie die Benzo[c]phenanthridine zudem antimikrobielle, antifungizide, antivirale und antiinflammatorische Eigenschaften besitzen. Zur Untersuchung der pharmakologischen Eigenschaften wurden die Verbindungen der allgemeinen Formeln I und II, sowie Verbindungen der Substanzklasse III in einem "in-vitro-Antitumor-Screening" des National Cancer Institute (NCI), Bethesda, Maryland, USA, untersucht. Getestet wurde gegen 60 verschiedene humanpathogene Tumorzellreihen, die neun Krebsarten entstammten (Leukämie, nichtkleinzelliges Lungenkarzinom, Dickdarmkrebs, ZNS-Krebs, Melanom, Eierstockkrebs, Nierenkrebs, Prostatakrebs, Brustkrebs). Zur Ermittlung der Wirksamkeit werden die Tumorzellen den Verbindungen über zwei Tage ausgesetzt und danach indirekt über die Bestimmung der Proteinbiomasse mit Sulforhodamin B (SRB) die Wachstumshemmung ermittelt. Unbehandelte Kulturen dienen als Referenz. It has been shown in the experiments carried out according to the invention that the phenanthroline derivatives described above have antitumoral properties. Due to their structural similarity, they are believed to have antimicrobial, like benzo [c] phenanthridines, possess antifungicidal, antiviral and anti-inflammatory properties. To investigate the pharmacological properties, the compounds of general formulas I and II, as well as compounds of the class III in an "in vitro antitumor screening" of National Cancer Institute (NCI), Bethesda, Maryland, USA, were investigated. It was tested against 60 different human pathogenic tumor cell lines from nine cancers (leukemia, non-small cell lung carcinoma, colorectal cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, breast cancer). To determine the effectiveness of the tumor cells are exposed to the compounds over two days and then determined indirectly by determining the protein biomass with sulforhodamine B (SRB), the growth inhibition. Untreated cultures are for reference.
Figure imgf000011_0001
Figure imgf000011_0001
Strukturformel der am National Cancer Institute (NCI) getesteten Verbindungen der erfindungsgemäßen Phenanthrolinderivate der Formeln I und II.  Structural formula of the compounds tested at the National Cancer Institute (NCI) phenanthroline derivatives of the invention of formulas I and II.
Bei den erfindungsgemäßen Untersuchungen wurden die Derivate zunächst in einer Konzentration von 1 μΜ an den 60 Zelllinien getestet. Es konnten für mehrere Derivate Wachstumshemmungen festgestellt werden. Überraschenderweise wiesen die erfindungsgemäßen Verbindungen Aktivitäten auf, die außerhalb der Kategorie von in ähnlicher Weise untersuchten Antitumorverbindungen liegen, so dass hier ein ganz neues Wirkungsspektrum erzielt wird. In the investigations according to the invention, the derivatives were first tested in a concentration of 1 μΜ on the 60 cell lines. Growth inhibition was found for several derivatives. Surprisingly, the compounds according to the invention exhibited activities which are outside the category of antitumor compounds investigated in a similar manner, so that a completely new spectrum of action is achieved here.
Tabelle I zeigt die Ergebnisse dieses Tests, ausgewählt für 7 verschiedene Derivate der erfindungsgemäßen Phenanthrolinderivate der Formeln I und II mit unterschiedlichen Resten in 11- Position sowie in 6-Position. Die jeweiligen Reste sind in den ersten beiden Zeilen dargestellt. Die linke Spalte zeigt die verwendeten Zelllinien aus 3 ausgewählten Tumorarten, Leukämie, Melanom, sowie Brustkrebs. Die Tabelle macht Aussagen über wachstumshemmende Wirkungen der entsprechenden Derivate mit ihren unterschiedlichen Resten.
Figure imgf000012_0001
Table I shows the results of this test, selected for 7 different derivatives of phenanthroline derivatives of the invention of formulas I and II with different residues in the 11-position and in the 6-position. The respective radicals are shown in the first two lines. The left column shows the cell lines used from 3 selected tumor types, leukemia, melanoma and breast cancer. The table makes statements about growth-inhibiting effects of the corresponding derivatives with their different residues.
Figure imgf000012_0001
Tabelle I: Zytotoxizitätstests des NCI an 60 Tumorzelllinien (c = 1 μΜ) mit Derivaten der Formeln I und II. Table I: Cytotoxicity tests of NCI on 60 tumor cell lines (c = 1 μΜ) with derivatives of formulas I and II.
Die ersten drei Derivate zeigen deutliche Wachstumshemmungen auf die Zellen der für das Beispiel ausgewählten Tumorarten, während die restlichen 4 Derivate keine bis nur sehr geringe wachstumshemmende Effekte auf diese Zellen haben. Hieraus lässt sich ableiten, dass ein 3- Halogenphenylrest in 11 -Position für die wachstumshemmende Wirkung der Phenanthrolinderivate der Formeln I und II essentiell ist. Weder Derivate mit Halogenatomen in 2- oder 4-Position (im Beispiel 2- Bromphenyl, bzw. 4-Bromphenyl), noch Derivate mit anderen funktionellen Gruppen in 3-Position des Phenylrings, noch der unsubstituierte Phenylring zeigen wachstumshemmende Effekte in diesem Ausmaß. Tabelle II zeigt die Ergebnisse dieses Tests, ausgewählt für 5 verschiedene Derivate der erfindungsgemäßen Phenanthrolinderivate der Formel III mit unterschiedlichen Resten in 11 -Position. Die Reste in 11 -Position sind in der ersten Zeile dargestellt. Die linke Spalte zeigt die verwendeten Zelllinien aus 3 ausgewählten Tumorarten, Leukämie, Melanom, sowie Brustkrebs. Die Tabelle macht Aussagen über wachstumshemmende Wirkungen der entsprechenden Derivate mit ihren unterschiedlichen Resten. The first three derivatives show marked growth inhibition on the cells of the tumor types selected for the example, while the remaining 4 derivatives have no to very little growth-inhibiting effects on these cells. From this it can be deduced that a 3-halophenyl radical in the 11 position is essential for the growth-inhibiting effect of the phenanthroline derivatives of the formulas I and II. Neither derivatives with halogen atoms in the 2- or 4-position (in the example 2-bromophenyl, or 4-bromophenyl), nor derivatives with other functional groups in the 3-position of Phenyl rings, nor the unsubstituted phenyl ring show growth-inhibiting effects to this extent. Table II shows the results of this test, selected for 5 different derivatives of phenanthroline derivatives of the formula III according to the invention with different radicals in the 11-position. The residues in position 11 are shown in the first line. The left column shows the cell lines used from 3 selected tumor types, leukemia, melanoma and breast cancer. The table makes statements about growth-inhibiting effects of the corresponding derivatives with their different residues.
Figure imgf000013_0001
Figure imgf000013_0001
Strukturformel der am National Cancer Institute (NCI) getesteten Verbindungen der erfindungsgemäßen Phenanthrolinderivate der Formel III. Structural formula of the tested at the National Cancer Institute (NCI) compounds of Phenanthrolinderivate invention of formula III.
Rest in 11-PositionRest in 11-position
Figure imgf000014_0001
Figure imgf000014_0001
Zelllinien Zellwachstum in Prozent Cell lines cell growth in percent
Leukämie  leukemia
CCRF-CEM 21,7 32,1 74,9 7,2 12,4  CCRF-CEM 21.7 32.1 74.9 7.2 12.4
HL-60(TB) 18,9 26,0 118,7 -0,9 13,9  HL-60 (TB) 18.9 26.0 118.7 -0.9 13.9
MOLT-4 2,3 11,9 90,1 -8,9 -0,9  MOLT-4 2.3 11.9 90.1 -8.9 -0.9
RPMI-8226 80,7 76,2 96,8 33,5 62,7  RPMI-8226 80.7 76.2 96.8 33.5 62.7
SR 11,1 15,3 83,5 13,1 7,8  SR 11.1 15.3 83.5 13.1 7.8
K-562 80,0 68,9 88,8 29,9 51,6  K-562 80.0 68.9 88.8 29.9 51.6
Mittelwert 35,8 38,4 92,1 12,3 24,6 Melanom  Mean 35.8 38.4 92.1 12.3 24.6 melanoma
LOX IMVI 41,0 37,9 89,3 -30,4 2,3  LOX IMVI 41.0 37.9 89.3 -30.4 2.3
MALME-3M 91,0 73,7 123,8 35,5 59,7  MALME-3M 91.0 73.7 123.8 35.5 59.7
M14 74,7 59,1 94,8 9,5 37,0  M14 74.7 59.1 94.8 9.5 37.0
MDA-MB-435  MDA-MB-435
SK-MEL-2 141,3 103,9 117,3 65,3 91,8  SK-MEL-2 141.3 103.9 117.3 65.3 91.8
SK-MEL-28 102,1 69,4 119,5 41,5 42,4  SK-MEL-28 102.1 69.4 119.5 41.5 42.4
SK-MEL-5 64 51,2 86,3 2,2 20,0  SK-MEL-5 64 51.2 86.3 2.2 20.0
UACC-257 124,5 78,0 126,3 30,9 69,8  UACC-257 124.5 78.0 126.3 30.9 69.8
UACC-62 79,3 45,2 99,1 - 41,0  UACC-62 79.3 45.2 99.1 - 41.0
Mittelwert 89,9 64,8 95,2 22,1 45,5  Mean 89.9 64.8 95.2 22.1 45.5
Brustkrebs breast cancer
MCF7 39,8 37,1 89,9 22,8 25,0  MCF7 39.8 37.1 89.9 22.8 25.0
MDA-MB-231/ATCC 112,0 77,1 90,8 - 74,9  MDA-MB-231 / ATCC 112.0 77.1 90.8-74.9
HS-578T 83,9 64,2 90,5 -2,5 - HS-578T 83.9 64.2 90.5 -2.5 -
BT-549 59,4 61,4 95,0 8,31 16,2 BT-549 59.4 61.4 95.0 8.31 16.2
T-47D 97,0 77,7 97,4 36 48,4  T-47D 97.0 77.7 97.4 36 48.4
MDA-MB-468 98,2 53,7 81,5 -23,6 35,6  MDA-MB-468 98.2 53.7 81.5 -23.6 35.6
Mittelwert 81,7 61,9 90,9 8,2 40,0  Mean 81.7 61.9 90.9 8.2 40.0
Mittelwert über alle Mean over all
eOZelllinlen 69,9 55,6 98,0 16,8 39,1  eO cell lines 69.9 55.6 98.0 16.8 39.1
Tabelle II: Zytotoxizitätstests des NCI an 60 Tumorzelllinien (c = 1 μΜ) mit Derivaten der Formel III. Table II: Cytotoxicity tests of NCI on 60 tumor cell lines (c = 1 μΜ) with derivatives of the formula III.
Die Tabelle II zeigt die besten Ergebnisse hinsichtlich einer wachstumshemmenden Wirkung für das Derivat mit dem Trimethoxyphenyl-Rest in 11 -Position. Das Derivat mit nur einer Methoxygruppe in meta-Position erzielt ebenfalls beachtliche Wachstumshemmungen. Das 11-Phenyl-Derivat hat nur eine geringe Wirkung, während sich eine Substitution in o-Position am Beispiel des 2,3-Dimethoxyphenyl- Derivates als nachteilig erweist. Hieraus lässt sich ableiten, dass zumindest in der meta-Position des 11- Phenylrings ein Substituent vorhanden sein muss. Durch die Ergebnisse der Tabelle I ist zu erwarten, dass der Ersatz von Methoxy- durch Halogen in Meta-Position ebenfalls zu guten wachstumshemmenden Effekten führt. Stellvertretend für einen fänfgliedrigen Heteroaromaten zeigt hier das 11-Furyl-Derivat gute zytotoxische Effekte. Table II shows the best results in terms of a growth-inhibitory effect for the derivative with the trimethoxyphenyl radical in the 11-position. The derivative with only one methoxy group in the meta position also achieves considerable growth inhibition. The 11-phenyl derivative has only a slight effect, while a substitution in the o-position on the example of the 2,3-dimethoxyphenyl derivative proves to be disadvantageous. From this it can be deduced that at least in the meta position of the 11-phenyl ring, a substituent must be present. From the results of Table I it can be expected that the replacement of methoxy by halogen in the meta position will also be good growth-inhibiting effects. The 11-furyl derivative shows good cytotoxic effects as a representative of a seeded heteroaromatic compound.
Des Weiteren ist aus den Tabellen I und II zu entnehmen, dass die hier getesteten erfindungsgemäßen Phenanthrolmderivate Selektivitäten für bestimmte Tumorarten besitzen. Am deutlichsten ausgeprägt ist eine wachstumshemmende Wirkung auf Tumorzellen der Leukämie. Ferner ist eine gewisse Selektivität für Tumorzellen des Melanoms und des Mammakarzinoms (Brustkrebs) zu erkennen. Diese Ergebnisse sind repräsentativ für alle 60 Zelllinien. Von den wirksamsten Verbindungen sind des Weiteren Dosis- Wirkungs-Beziehungen für 5 Konzentrationen bestimmt worden. Die GI5o (growth Inhibition 50%) beschreibt dabei die Konzentration der Testsubstanz, die für eine Hemmung des Zellwachstums um 50% erforderlich ist. Daraus wird der sog. "meangraph-midpoint" (MGJVIID) ermittelt, der als Mittelwert der logarithmierten GI5o-Werte einem durchschnittlichen Ansprechverhalten aller 60 Zelllinien auf die untersuchte Testsubstanz entspricht [Boyd und Pauli, Drug. Develop. Res., 34, (1995) 91-109,] Furthermore, it can be seen from Tables I and II that the phenanthrolder derivatives according to the invention tested here have selectivities for certain tumor types. Most pronounced is a growth inhibitory effect on tumor cells of leukemia. Furthermore, a certain selectivity for tumor cells of the melanoma and mammary carcinoma (breast cancer) can be seen. These results are representative of all 60 cell lines. Furthermore, among the most potent compounds, dose-response relationships for 5 concentrations have been determined. The GI 5 o (growth inhibition 50%) here describes the concentration of test substance required for inhibiting cell growth by 50%. From this, the so-called "meangraph-midpoint" (MGJVIID) is determined which, as the mean of the logarithmized GI 5 o values, corresponds to an average response of all 60 cell lines to the tested test substance [Boyd and Pauli, Drug. Develop. Res., 34, (1995) 91-109,]
Σ log GI50 Σ log GI 50
mD =— w- m D = - w
Mit dieser Größe lässt sich die Aktivität einer Verbindung in dem verwendeten Testsystem charakterisieren und quantitativ mit der Aktivität anderer Verbindungen vergleichen (Tabelle 3). Die folgende Tabelle zeigt 4 Derivate der Formeln I und III mit ihren verwendeten Codes, die für die entsprechenden Substanzen ermittelten meangraph-midpoints und die daraus errechneten GI5o- Werte. With this size, the activity of a compound in the test system used can be characterized and compared quantitatively with the activity of other compounds (Table 3). The following table shows 4 derivatives of the formulas I and III with their codes used, the meangraph midpoints determined for the corresponding substances and the GI 5 o values calculated therefrom.
Code MG MID Σ^ [μΜ] Code MG MID Σ ^ [μΜ]
P4 -5,09 8,13 P4 -5.09 8.13
P5 -5,57 2,69  P5 -5.57 2.69
P5-0 -5,07 8,51 P5-0 -5.07 8.51
P16 -5,42 3,80 P16 -5.42 3.80
P26 -5,22 6,02  P26 -5.22 6.02
Fagaronin -5,00 9,48  Fagaronin -5.00 9.48
Legende zur Tabelle 3 : Legend to Table 3:
P4 = 6-Amino-l l,12-dihydropyrido[3,4-c][l,9]phenanthrolin, P5 = 6-Amino-l l-(3-bromphenyl)-l 1,12- dihydro-pyrido-[3,4-c] [l,9]phenanthrolin, P5-0 = 1 l-(3-bromphenyl)-6-oxo-5, 6,11,12- tetrahydropyrido[3,4-c] [l,9]phenanthrolin, P16 = 6-Amino-l l-(3-chlorphenyl)-l 1,12-dihydropyrido- [3,4-c] [l,9]phenanthrolin, P26 = 6-Amino-l l-(3,4-di-chlorphenyl)-l 1, 12-dihydropyrido-[3,4-c]- [1 ,9]phenanthrolin. P4 = 6-amino-1,11,12-dihydropyrido [3,4-c] [l, 9] phenanthroline, P5 = 6-amino-1- (3-bromophenyl) -1,12-dihydro-pyrido- [3,4-c] [l, 9] phenanthroline, P5-0 = 1 l- (3-bromophenyl) -6-oxo-5, 6, 11, 12- tetrahydropyrido [3,4-c] [l, 9] phenanthroline, P16 = 6-amino-1- (3-chlorophenyl) -1,12-dihydropyrido [3,4-c] [l, 9] phenanthroline , P26 = 6-Amino-l- (3,4-di-chlorophenyl) -1,12-dihydropyrido [3,4-c] - [1, 9] phenanthroline.
Zusätzlich zu den erfindungsmäßen Verfindungungen wurde Fagaronin getestet, ein pflanzliches Benzo[c]phenanthridin-Alkaloid, das als Leitsubstanz für die Entwicklung synthetischer Benzo[c]phenanthridin-Derivate gilt (Pommier, Y. Nat. Rev. Cancer, 6, (2006), 789; Pommier, Y. Chem. Rev. 109, (2009), 2984). Festzuhalten ist, dass alle Derivate der erfindungsgemäßen Phenathroline, für die Dosis-Wirkungskurven bestimmt worden sind, eine bessere wachstumshemmende Wirkung aufweisen, als der Naturstoff Fagaronin. In addition to the inventions Fagaronin was tested, a vegetable benzo [c] phenanthridine alkaloid, which is considered as a lead compound for the development of synthetic benzo [c] phenanthridine derivatives (Pommier, Y. Nat Rev. Cancer, 6, (2006) , 789; Pommier, Y. Chem. Rev. 109, (2009), 2984). It should be noted that all derivatives of the phenathrolines according to the invention, for which dose-response curves have been determined, have a better growth-inhibiting effect than the natural product fagaronin.
Beispielhaft für 6-Amino-l l-(3-bromphenyl)-l l,12-dihydropyrido[34-c][l,9]phenanthrolin sind die Dosis-Wirkungs-Kurven in der in den Abbildungen 1 bis 9 wiedergegeben. Die neun verschiedenen Abbildungen beinhalten die verschiedenen Krebsformen. Aufgetragen ist jeweils das prozentuale Wachstum in Abhängigkeit von der Konzentration der Verbindung (als logio der molaren Konzentrationen). Die einzelnen Kurven einer jeden Krebsart sind verschiedene Zelllinien dieser Krebsform, die als Legenden in ihren üblichen Abkürzungen erscheinen. Horizontale Linien in den Abbildungen bedeuten Prozentwachstum +100, +50, 0, -50, -100. 100 % Wachstum bedeutet z.B. keinen Unterschied zum Wachstum nach zwei Tagen ohne Substanzzusatz. Man erkennt bei den einzelnen Kurven, dass sich mit steigenden Konzentrationen der Substanz das Prozentwachstum verkleinert. Illustrative of 6-amino-1- (3-bromophenyl) -1,12-dihydropyrido [34-c] [l, 9] phenanthroline are the dose-response curves shown in Figures 1-9. The nine different illustrations contain the different cancers. In each case, the percentage growth is plotted as a function of the concentration of the compound (as logio of the molar concentrations). The individual curves of each cancer are different cell lines of this cancer form, which appear as legends in their usual abbreviations. Horizontal lines in the figures mean percent growth +100, +50, 0, -50, -100. 100% growth means e.g. no difference to growth after two days without added substance. It can be seen from the individual curves that the percentage growth decreases with increasing concentrations of the substance.
Ein besonderer Vorteil der erfindungsgemäßen Phenanthrolinderivate ist ihre verbesserte Wasserlöslichkeit im Vergleich zu den 6-Aminobenzo[c]phenanthridinen. Hierbei ist vor allem die Löslichkeit in sauren wässrigen Medien zu nennen (2-20 mM in Phosphatpuffer pH=2, und noch 0,01- 0,5 mmol in Phosphatpuffer pH=4), welche auf 2 zusätzliche, protonierbare Stickstoffatome zurückzuführen ist. Bei pH 7,4 konnten für zahlreiche Derivate Löslichkeiten im unteren mikromolaren Bereich (< 1-15 μΜ) gefunden werden, die Löslichkeit der 6-Aminobenzo[c]phenanthridine bei diesem pH- Wert liegt vorherrschend im nanomolaren Bereich. Die Abbildung 10 zeigt 4 Einzelgrafiken, stehend für 4 Phosphatpuffersysteme mit verschiedenen pH- Werten, in denen jeweils die Löslichkeiten der erfindungsgemäßen 6-Amino-l l,12-dihydropyrido[3,4-c] [l,9]phenanthroline auf der y-Achse aufgetragen sind, während auf der x-Achse die verschiedene Derivate mit unterschiedlichen Resten in 11 -Position (3a: R = phenyl, 3b: R = 3-methoxyphenyl, 3d: R = 2,3-dimethoxyphenyl, 3e: R = 3,5- dimethoxyphenyl, 3f: R = 3,4,5-trimethoxyphenyl, 3g: R = 2,4,6-trimethoxyphenyl, 3h: R = furyl, 3i: R = thienyl, 3j: R = 3-bromophenyl, 3k: R = 4-bromophenyl, 31: R = 3-chlorophenyl, 3m: R = 4- fluorophenyl, 3n: R = biphenyl, 3o: R = propyl) zu sehen sind. Von den erfindungsgemäßen Phenanthrolinderivaten wurden des Weiteren logP-Werte als ein Maß für die Lipophilie der Substanzklasse bestimmt. Hierbei wurden sechs unterschiedliche 6-Amino-l 1,12- dihydropyrido[3,4-c] [l,9]phenanthroline mit unterschiedlichen Resten in 11 -Position mit den korrespondierenden Benzo[c]phenanthridinen verglichen. Die Abbildung 11 zeigt die logP-Werte auf der y- Achse, aufgetragen gegen die Derivate, die sich in den sechs benannten Resten in 11 -Position unterscheiden, jeweils für die beiden verglichenen Substanzklassen. Desweiteren ist der Mittelwert (MW) aufgetragen. A particular advantage of the phenanthroline derivatives according to the invention is their improved water solubility in comparison to the 6-aminobenzo [c] phenanthridines. Here, the solubility in acidic aqueous media should be mentioned in particular (2-20 mM in phosphate buffer pH = 2, and still 0.01-0.5 mmol in phosphate buffer pH = 4), which is due to 2 additional, protonatable nitrogen atoms. At pH 7.4 solubilities in the lower micromolar range (<1-15 μΜ) could be found for numerous derivatives, the solubility of the 6-Aminobenzo [c] phenanthridine at this pH is predominantly in the nanomolar range. Figure 10 shows 4 individual graphics, standing for 4 phosphate buffer systems with different pH values, in each of which the solubilities of the inventive 6-amino-l l, 12-dihydropyrido [3,4-c] [l, 9] phenanthroline on the y -Axis are plotted, while on the x-axis the various derivatives with different residues in position 11 (3a: R = phenyl, 3b: R = 3-methoxyphenyl, 3d: R = 2,3-dimethoxyphenyl, 3e: R = 3,5-dimethoxyphenyl, 3f: R = 3,4,5-trimethoxyphenyl, 3g: R = 2,4,6-trimethoxyphenyl, 3h: R = furyl, 3i: R = thienyl, 3j: R = 3-bromophenyl, 3k: R = 4-bromophenyl, 31: R = 3-chlorophenyl, 3m: R = 4-fluorophenyl, 3n: R = biphenyl, 3o: R = propyl). Furthermore, logP values of the phenanthroline derivatives according to the invention were determined as a measure of the lipophilicity of the substance class. Six different 6-amino-1,12-dihydropyrido [3,4-c] [l, 9] phenanthrolines with different residues in position 11 were compared with the corresponding benzo [c] phenanthridines. Figure 11 shows the logP values on the y-axis plotted against the derivatives differing in the six named residues in the 11-position, respectively, for the two substance classes being compared. Furthermore, the mean value (MW) is plotted.
Aus der Grafik wird ersichtlich, dass die logP- Werte der erfindungsgemäßen 6-Amino-l 1,12- dihydropyrido[3,4-c][l,9]phenanthroline im Mittel ungefähr um den Wert 2 niedriger sind als bei den entsprechenden Benzo[c]phenanthridinen. It can be seen from the graph that the logP values of the 6-amino-1,12-dihydropyrido [3,4-c] [l, 9] phenanthrolines according to the invention are on average about 2 lower than for the corresponding benzo [c] phenanthridines.
Dies ist von enormer Wichtigkeit, betrachtet man die Eignung der Substanzklasse als Arzneistoff und vor allem seine orale Bioverfügbarkeit. Nach der "Rule of Five" von Lipinski (Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug. Deliv. Rev. 46 (2001) , 3-26), einer allgemein anerkannten Faustregel für die Abschätzung der oralen Bioverfügbarkeit eines möglichen Arzneistoffs, ist ein Stoff oral bioverfügbar, wenn er nicht mehr als fünf Donatoren von Wasserstoffbrückenbindungen (z. B. OH- oder NH-Gruppen), nicht mehr als zehn Akzeptoren von Wasserstoffbrückenbindungen (z. B. Sauerstoff- oder Stickstoffatome), eine Molekülmasse von nicht mehr als 500 g/mol, sowie einen Verteilungskoeffizienten (logP) zwischen Oktanol und Wasser (Oktanol- Wasser- Verteilungs-koeffizient) von maximal 5 besitzt. Die untersuchten erfindungsgemäßen Derivate liegen alle innerhalb der Grenzbereiche der "Rule of Five" und eignen sich danach als oral applizierbare Arzneistoffe, z.B. in Form von Lösungen, Tabletten, Kapseln, etc. This is of tremendous importance considering the suitability of the substance class as a drug and especially its oral bioavailability. According to the "Rule of Five" by Lipinski (Lipinski, CA; Lombardo, F. Dominy, BW; Feeney, PJ Adv. Drug Deliv., Rev. 46 (2001), 3-26), a generally accepted rule of thumb for the Estimating the Oral Bioavailability of a Potential Drug, a substance is orally bioavailable if it contains no more than five hydrogen-bond donors (eg, OH or NH groups), no more than ten hydrogen-bond acceptors (eg, oxygen donors). or nitrogen atoms), a molecular weight of not more than 500 g / mol, and a distribution coefficient (logP) between octanol and water (octanol-water partition coefficient) of 5 or less. The examined derivatives according to the invention are all within the limits of the "Rule of Five" and are then suitable as orally applicable drugs, e.g. in the form of solutions, tablets, capsules, etc.
Die Abbildungen zeigen Dosis-Wirkungs-Kurven von 9 verschiedenen Tumorarten aus dem 5-dose- assay (NCI) für 6-Amino-l l-(3-bromphenyl)-l l,12-dihydropyrido[3,4-c][l,9]phenanthrolin. The figures show dose-response curves of 9 different tumor types from the 5-dose assay (NCI) for 6-amino-1- (3-bromophenyl) -II, 12-dihydropyrido [3,4-c] [l , 9] phenanthroline.
Kurze Beschreibung der Abbildungen Brief description of the illustrations
Abb. 1 : Dosis-Wirkungs-Kurven für Leukämie-Tumore aus dem 5-dose-assay (NCI) für 6-Fig. 1: Dose-response curves for leukemia tumors from the 5-dose assay (NCI) for 6-
Amino- 11 -(3 -bromphenyl)- 11,12-dihydropyrido [3 ,4-c] [ 1 ,9]phenanthrolin Amino-11- (3-bromophenyl) -11,12-dihydropyrido [3,4-c] [1,9] phenanthroline
Abb. 2: Dosis-Wirkungs-Kurven für nicht-kleinzellige Bronchialkarzinome aus dem 5-dose- assay (NCI) für 6-Amino-l l-(3-bromphenyl)-l l,12-dihydropyrido[3,4- c] [ 1 ,9]phenanthrolin Fig. 2: Dose-response curves for non-small cell lung carcinomas from the 5-dose assay (NCI) for 6-amino-1- (3-bromophenyl) -II, 12-dihydropyrido [3,4-c] [1, 9] phenanthroline
Abb. 3: Dosis-Wirkungs-Kurven für Colonkarzinome aus dem 5-dose-assay (NCI) für 6-Amino-FIG. 3: dose-response curves for colon carcinomas from the 5-dose assay (NCI) for 6-amino
11 -(3 -bromphenyl)- 11 , 12-dihydropyrido [3 ,4-c] [ 1 ,9]phenanthrolin 11- (3-bromophenyl) -11,12-dihydropyrido [3,4-c] [1,9] phenanthroline
Abb. 4: Dosis-Wirkungs-Kurven für ZNS-Krebs aus dem 5-dose-assay (NCI) für 6-Amino-l l-FIG. 4: dose-response curves for CNS cancer from the 5-dose assay (NCI) for 6-amino-1-ol
(3 -bromphenyl)- 11,12-dihydropyrido [3 ,4-c] [ 1 ,9]phenanthrolin (3-Bromophenyl) -11,12-dihydropyrido [3,4-c] [1,9] phenanthroline
Abb. 5: Dosis-Wirkungs-Kurven für Melanome aus dem 5-dose-assay (NCI) für 6-Amino-l l-FIG. 5: dose-response curves for melanomas from the 5-dose assay (NCI) for 6-amino-1-ol
(3 -bromphenyl)- 11,12-dihydropyrido[3 ,4-c] [ 1 ,9]phenanthrolin (3-Bromophenyl) -11,12-dihydropyrido [3,4-c] [1,9] phenanthroline
Abb. 6: Dosis-Wirkungs-Kurven für Nierenzellkarzinome aus dem 5-dose-assay (NCI) für 6-Fig. 6: Dose-response curves for renal cell carcinomas from the 5-dose assay (NCI) for 6-
Amino- 11 -(3 -bromphenyl)- 11,12-dihydropyrido [3 ,4-c] [ 1 ,9]phenanthrolin Amino-11- (3-bromophenyl) -11,12-dihydropyrido [3,4-c] [1,9] phenanthroline
Abb. 7: Dosis-Wirkungs-Kurven für Ovarialkarzinome aus dem 5-dose-assay (NCI) für 6-FIG. 7: dose-response curves for ovarian carcinomas from the 5-dose assay (NCI) for 6-
Amino- 11 -(3 -bromphenyl)- 11,12-dihydropyrido [3 ,4-c] [ 1 ,9]phenanthrolin Amino-11- (3-bromophenyl) -11,12-dihydropyrido [3,4-c] [1,9] phenanthroline
Abb. 8: Dosis-Wirkungs-Kurven für Prostatakarzinome aus dem 5-dose-assay (NCI) für 6-Fig. 8: Dose-response curves for prostate cancer from the 5-dose assay (NCI) for 6-
Amino- 11 -(3 -bromphenyl)- 11,12-dihydropyrido [3 ,4-c] [ 1 ,9]phenanthrolin Amino-11- (3-bromophenyl) -11,12-dihydropyrido [3,4-c] [1,9] phenanthroline
Abb. 9: Dosis-Wirkungs-Kurven für Mammakarzinome aus dem 5-dose-assay (NCI) für 6-FIG. 9: dose-response curves for mammary carcinomas from the 5-dose assay (NCI) for 6-
Amino- 11 -(3 -bromphenyl)- 11,12-dihydropyrido [3 ,4-c] [ 1 ,9]phenanthrolin Amino-11- (3-bromophenyl) -11,12-dihydropyrido [3,4-c] [1,9] phenanthroline
Abb. 10: pH-abhängige Löslichkeiten der 6- Amino- 11,12-dihydropyrido [3,4- c] [ 1 ,9]phenanthroline Fig. 10: pH-dependent solubilities of the 6-amino-11,12-dihydropyrido [3,4-c] [1, 9] phenanthrolines
Abb. 11 : logP-Werte in Abhängigkeit von den Resten in 11 -Position Fig. 11: LogP values as a function of the residues in 11 position

Claims

Patentansprüche claims
1. Verbindung der allgemeinen Formel I oder II  1. Compound of the general formula I or II
Figure imgf000019_0001
Figure imgf000019_0001
wobei R1 gleich einem Phenylring der Formel wherein R 1 is a phenyl ring of the formula
Figure imgf000019_0002
Figure imgf000019_0002
ist, der mindestens einen Substituenten R ausgewählt aus der Gruppe Cl, Br oder I in metaStellung trägt, wobei RY, welches gleich oder verschieden sein kann, gleich H, OH, OMe, OEt oder Halogen ist; sowie Verbindung der allgemeinen Formel III oder IV, is at least one substituent R selected from the group Cl, Br or I in the meta position, wherein R Y , which may be the same or different, is H, OH, OMe, OEt or halogen; and compound of general formula III or IV,
Figure imgf000019_0003
wobei R1 entweder gleich einem Phenylring der Formel
Figure imgf000019_0003
where R 1 is either equal to a phenyl ring of the formula
Figure imgf000020_0001
ist, der mindestens einen Substituenten RY in meta-Stellung trägt, wobei RY, welches gleich oder verschieden sein kann, gleich H, OH, OMe, OEt oder Halogen ist oder gleich einem fünfgliedrigen aromatischen Heterocyclus der Formel
Figure imgf000020_0001
is that carries at least one substituent R Y in the meta position, wherein R Y , which may be identical or different, is H, OH, OMe, OEt or halogen or a five-membered aromatic heterocycle of the formula
Figure imgf000020_0002
ist, wobei Z gleich H, F, Cl, Br, I, NHX, OX, SX
Figure imgf000020_0002
where Z is H, F, Cl, Br, I, NHX, OX, SX
wobei X gleich einem H, Dimethylaminoalkyl-, Diethyaminoalkyl-, ro-(l,3-diazol-l-yl)-alkyl-, Hydroxyalkyl-, Alkoxyalkyl-, Thiolalkyl-, Alkylthioalkylgruppe ist,  wherein X is H, dimethylaminoalkyl, diethyaminoalkyl, ro (1,3-diazol-1-yl) alkyl, hydroxyalkyl, alkoxyalkyl, thiolalkyl, alkylthioalkyl,
wobei Alkyl gleich Methyl, Ethyl oder Propyl  where alkyl is methyl, ethyl or propyl
und wobei A gleich O oder S ist,  and where A is O or S,
sowie deren pharmazeutisch verträgliche Salze, Solvate und Prodrugs.  and their pharmaceutically acceptable salts, solvates and prodrugs.
2. Verfahren zur Herstellung einer Verbindung nach Anspruch 1, umfassend 2. A process for the preparation of a compound according to claim 1, comprising
mindestens die folgenden Schritte:  at least the following steps:
(i) Umsetzung von substituierten Aldehyden der allgemeinen Formel R1 -CHO (V) mit substituierten 4-Methylpyridin-3-carbonitrilen der allgemeinen Formel (i) Reaction of substituted aldehydes of the general formula R 1 -CHO (V) with substituted 4-methylpyridine-3-carbonitriles of the general formula
Figure imgf000020_0003
in aprotischen bipolaren Lösungsmitteln in Gegenwart von Basen zu einer Verbindung der allgemeinen Formel
Figure imgf000020_0003
in aprotic bipolar solvents in the presence of bases to give a compound of the general formula
Figure imgf000021_0001
Figure imgf000021_0001
(ii) Isolierung der Produkte und Derivatisierung an Position 6 unter Einfügen der Reste R zu den Derivaten mit A- oder Z-Substitution in 6-Position, gemäß der Formel I bis IV, wobei (Ii) Isolation of the products and derivatization at position 6 with the introduction of the radicals R to the derivatives with A or Z substitution in the 6-position, according to the formula I to IV, wherein
R1 ein H, ein cyclischer oder acyclischer, verzweigter oder unverzweigter aliphatischer Kohlenwasserstoffrest, einfach oder mehrfach substituiert, ein aromatischer carbocyclischer oder heterocyclischer Rest, einfach oder mehrfach substituiert ist, und R 1 is an H, a cyclic or acyclic, branched or unbranched aliphatic hydrocarbon radical, mono- or polysubstituted, an aromatic carbocyclic or heterocyclic radical, monosubstituted or polysubstituted, and
R2 und R3, gleich oder verschieden sein können und ein H, Alkyloxyrest, Alkylenoxyrest, Halogenatom oder eine Nitrogruppe ist, und R 2 and R 3 may be the same or different and is H, alkyloxy, alkyleneoxy, halogen or nitro, and
R4 ein H, eine Monoamino-, Alkylamino-, Dialkylamino-, (Dialkyl-)aminoalkylamin-, Alkyl-, Alkoxy-, (Dialkyl-)aminoalkyloxy-, Hydroxy-, Hydroxyalkylamino-, Hydroxyalkyloxy-, Thiol-, (Dialkyl-)aminoalkylthio-, Thiolalkyl-, Alkylthioalkylgruppe oder ein Halogenatom ist. R 4 is an H, a monoamino, alkylamino, dialkylamino, (dialkyl) aminoalkylamine, alkyl, alkoxy, (dialkyl) aminoalkyloxy, hydroxy, hydroxyalkylamino, hydroxyalkyloxy, thiol, (dialkyl) ) is aminoalkylthio, thiolalkyl, alkylthioalkyl or halogen.
3. Verfahren nach Anspruch 2, wobei zwischen den beiden Schritten (i) und (ii) optional der Verfahrensschritt 3. The method according to claim 2, wherein between the two steps (i) and (ii) optionally the method step
(i.a.) Dehydrierung und Isolierung der hieraus resultierenden Produkte der allgemeinen Formel (ia) dehydration and isolation of the resulting products of the general formula
Figure imgf000022_0001
eingeführt sein kann.
Figure imgf000022_0001
can be introduced.
4. Verfahren nach Anspruch 2 oder 3, wobei das aprotische dipolare Lösungsmittel vorzugsweise ein Amid wie Dimethylformamid, Dimethylacetamid, Diethylacetamid, Hexamethylphosphorsäuretrisamid oder ein Harnstoff wie Tetramethylharnstoff, 1,3- Dimethyltetrahydropyrimidin-2-οη und 1,3-Dimethylimidazolidinon oder ein Dimethylsulfoxid ist, und wobei die Base ein Alkali- oder Erdalkalihydrid wie Natriumhydrid, Alkaliamid wie Natriumamid, Natriummethylacetamid, Alkali-, Erdalkali- oder Aluminiumalkoholat wie Kalium- tert-butylat, Natriummethylat, Natriumethylat oder Aluminiumethylat ist. 4. The method of claim 2 or 3, wherein the aprotic dipolar solvent is preferably an amide such as dimethylformamide, dimethylacetamide, diethylacetamide, Hexamethylphosphorsäuretrisamid or a urea such as tetramethylurea, 1,3-dimethyltetrahydropyrimidin-2-οη and 1,3-dimethylimidazolidinone or a dimethyl sulfoxide and wherein the base is an alkali or alkaline earth metal hydride such as sodium hydride, alkali metal amide such as sodium amide, sodium methylacetamide, alkali metal, alkaline earth metal or aluminum alkoxide such as potassium tert-butoxide, sodium methoxide, sodium ethylate or aluminum ethylate.
5. Verbindung erhältlich durch ein Verfahren nach einem der Ansprüche 2 bis 4. 5. A compound obtainable by a process according to any one of claims 2 to 4.
6. Verbindung nach Anspruch 1 oder 5 zur Verwendung als Arzneimittel. 6. A compound according to claim 1 or 5 for use as a medicament.
7. Verbindung nach Anspruch 1 oder 5 zur Verwendung bei der Behandlung einer Erkrankung ausgewählt aus einer Gruppe bestehend aus mikrobiellen, fungiziden, viralen und/oder inflammatorischen Erkrankungen. A compound according to claim 1 or 5 for use in the treatment of a disease selected from a group consisting of microbial, fungicidal, viral and / or inflammatory diseases.
8. Verbindung nach Anspruch 1 oder 5 zur Verwendung bei der Behandlung von Krebs. A compound according to claim 1 or 5 for use in the treatment of cancer.
9. Verbindung nach Anspruch 6, wobei der Krebs ausgewählt ist aus einer Gruppe bestehend aus Leukämie, Melanom oder Mammakarzinom. The compound of claim 6, wherein the cancer is selected from a group consisting of leukemia, melanoma or breast carcinoma.
10. Pharmazeutische Zusammensetzung enthaltend mindestens eine Verbindung nach einem der Ansprüche 1 , 5 bis 9 in Kombination mit einem geeigneten Hilfsstoff. 10. A pharmaceutical composition containing at least one compound according to any one of claims 1, 5 to 9 in combination with a suitable excipient.
PCT/EP2013/057212 2012-04-05 2013-04-05 New pyrido [3.4-c] [1.9] phenanthroline and 11, 12 dihydropyrido [3.4 -c] [1.9] phenanthroline derivatives and the use thereof, particularly for treating cancer WO2013150140A1 (en)

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CA2869426A CA2869426C (en) 2012-04-05 2013-04-05 New pyrido [3,4-c] [1,9] phenanthroline and 11, 12 dihydropyrido [3,4 -c] [1,9] phenanthroline derivatives and the use thereof, particularly for treating cancer
EP13717459.5A EP2834240B1 (en) 2012-04-05 2013-04-05 Novel pyrido[3,4-c][1,9]phenanthroline- and 11,12-dihydropyrido[3,4-c][1,9]phenanthroline- derivatives and their use, in particular, for the treatment of cancer
ES13717459.5T ES2636469T3 (en) 2012-04-05 2013-04-05 New derivatives of pyrido [3,4-c] [1,9] phenanthroline and 11,12-dihydropyrid [3,4-c] [1,9] phenanthroline and their use, particularly for the treatment of cancer
AU2013244918A AU2013244918B2 (en) 2012-04-05 2013-04-05 New pyrido [3.4-c] [1.9] phenanthroline and 11, 12 dihydropyrido [3.4 -c] [1.9] phenanthroline derivatives and the use thereof, particularly for treating cancer
US14/390,661 US9062054B2 (en) 2012-04-05 2013-04-05 Pyrido [3,4-C] [1,9] phenanthroline and 11, 12 dihydropyrido [3,4-C] [1,9] phenanthroline derivatives and the use thereof, particularly for treating cancer

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